JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY 2003, 54, Suppl 4, 155164 www.jpp.krakow.pl
E. Z. DAJANI,
, T. G. SHAHWAN,
1, 2
, N. E. DAJANI,
1, 3
1, 3
PROSTAGLANDINS AND BRAIN-GUT AXIS
1
International Drug Development Consultants (IDDC) Corporation, Long Grove, Illinois. 2
Gastroenterology Section, Loyola University Medical Center, Maywood, Illinois. 3
University of Illinois School of Medicine, Peoria, Illinois, USA
Prostaglandins
(PGs)
have
well
documented
physiological
and
pharmacological
actions on the gastrointestinal (GI) tract. This communication reviews the evidence for peripheral and central nervous system (CNS) physiological actions of PGs in
order to determine their role in the brain-gut axis, if any. PGs are widely distributed
in
nearly
all
cells
peripherally
and
centrally.
Laboratory
and
clinical
evidence
indicate that there is a direct relationship between altered GI physiological functions and peripheral PGs biosynthesis. Either local or parenteral administration of natural
E-series PGs alters GI physiological functions particularly those relating to mucosal defense. Furthermore, the cyclooxygenase enzymes (COX), which are responsible for the PGs biosynthesis, have been localized in the brain as well as peripherally.
However, increased levels of PGs in the brain have been associated with pathological
processes such as inflammation, pain, fever and addiction. Although PGs have been
shown to modulate CNS effects of catecholaminergic, serotoninergic and cholinergic
neurons, there is no meaningful information concerning their direct central effect on
GI function. The evidence for a clear physiological role of central PGs on the GI tract is not convincing. At this time, we conclude that PGs primarily manifest their activity on the GI tract by peripheral rather than by central mechanisms.
Key
w o r d s : Addiction, CNS, COX, cyclooxygenase, cytoprotection, fever, inflammation, mucosal protection, pain, prostaglandins, PGE2, PGF2alpha, PGD2, thromboxane B2, TXB2, stress ulcers
INTRODUCTION
Prostaglandins constitute a family of unsaturated fatty acids with 20-carbon skeleton. Prostaglandins are found in almost every mammalian cell and are
156
considered locally acting hormones (autacoids). They are synthesized on demand and subsequently inactivated at or near the sites of their synthesis. Prostaglandins are
metabolically
unstable
compounds
and
are
not
stored.
Because
of
their
omnipresence in nearly all cells, PGs possess wide variety of physiological and pharmacological action, which are occasionally troublesome in their clinical use as drugs (1). There is clear evidence that PGs have local and systemic action affecting GI physiology (2). However, the role of central PGs in the regulations of GI physiology and particularly mucosal defense is not clearly understood. The purpose of this communication is to review the evidence for a CNS role of PGs in GI physiology and pathophysiology in order to examine their role on the braingut axis, if any. Brain-Gut Axis Concept The concept supporting the existence of functionally important brain-gut axis was originally proposed to account for the fact that several peptides including bombesin, neurotensin and calcitonin-gene-related peptide occur both in brain and gut and seem to exert opposite actions on gut function when administered centrally and peripherally (3 - 5). Support for this concept is derived from clinical and laboratory studies showing that stress ulcer formation could be prevented by anxiolytic and antidepressant drugs. The reduction of anxiety, which is associated with the stressful stimuli, occurs by a direct effect on the CNS as shown by the inhibitory effects of a centrally administered imipramine on stress ulcer formation (6,
7).
Furthermore,
the
phenothiazine
tranquilizer
thiopropazoate
had
been
demonstrated to significantly potentiate the anti-ulcer action of cimetidine (a histamine-H2-receptor antagonist) and propantheline (a peripheral anticholinergic drug) against stress ulcers (8). These laboratory studies indicate that the CNS mediated pharmacological actions of thiopropazoate potentiated the peripheral GI protective action of the anti-ulcer drugs cimetidine and propantheline, which provides further support for the concept of brain-gut axis (8). Several lines of evidence indicate the involvement of dopamine in peripheral and central action of many drugs affecting the brain-gut axis (5, 9). As is shown in Table 1, there is laboratory and clinical evidence that peripheral and central dopamine
deficiency
is
associated
with
duodenal
ulcers
(9,
10).
Since
prostaglandins and other eicosanoids are involved in the presynaptic release of the neurotransmitters dopamine and serotonin (11), it is possible that some of their physiological action on the gut may be mediated by these neurotransmitters. However, the effects of central administration of PGs on dopamine-mediated effects on the GI tract have not yet been adequately investigated. Although PGs, growth factors and hormones possess direct cellular protective effects
on
the
GI
tract
that
is
independent
of
a
central
influence,
there
is
preliminary evidence which indicates that the CNS plays a contributory role towards this cytoprotection. In their cytoprotective study with gastric mucosal
157
cells, Bodis et al. (12) showed that intact peripheral innervations are needed for the maximum demonstration of the prostacyclin-induced gastric cytoprotection.
Table 1. Prostaglandins, Central Dopamine, Peptic Ulcer and Brain-Gut Axis l
Prostaglandins are involved in the presynaptic release of the neurotransmitters dopamine and serotonin.
l
Central deficiency of dopamine, common in Parkinson Disease Patients, is positively associated with of peptic ulcer (9).
l
Cysteamine
and
propionitrile
decrease
tissue
concentration
of
central
and/or
peripheral
dopamine. These substances induce duodenal ulcers formation in animals (10).
l
Psychiatric patients, who presumably have increased central dopamine concentration rarely develop peptic ulcer (9).
Szabo S, et al. (9, 10).
E-Prostaglandins and Gastrointestinal Physiology Prostaglandins of the E-series are the principal autacoids localized in the GI tract
and
have
several
well-characterized
physiological
actions
(1).
E-series
prostaglandins inhibit basal and stimulated acid secretion and protect the GI mucosa
from
injury
induced
by
noxious
agents.
E-
and
F-series
PGs
have
opposing dose-related effects on the lower esophageal sphincter and circular intestinal muscle causing relaxation and contractions, respectively (1, 13, 14). Other physiological effects of PGEs include an increase in hepatic blood flow, contraction of the gallbladder, relaxation of the sphincter of oddi, inhibition of pancreatic secretion and insulin release, and reduced absorption and induced secretion of electrolytes and water in the jejunum, and ileum, but not the colon (Table 2). A direct relationship exists between altered GI physiological function and prostaglandin synthesis (15, 16). For example, the nonsteroidal anti-inflammatory drugs (NSAIDs)-induced PGs depletion in the GI tract results in gastroduodenal ulceration and/or ulcer related GI complication (Table 3; 17). The administration of
natural
or
synthetic
PGEs,
either
by
parenteral,
oral
or
local
routes,
can
overcome the GI toxicity associated with the mucosal depletion of PGEs induced by NSAIDs (18 - 20). In addition, systemic or topical administration of natural and
synthetic
PGEs
analogs
can
reproduce
their
well-characterized
GI
physiological actions on the inhibition of acid secretion and mucosal protection (2, 20). The fact that mucosal protection by PGs is demonstrated in-vitro on isolated
gastric
and
duodenal
cells
clearly
supports
the
idea
that
mucosal
protection by PGs is a consequence of a direct action on PGs on the cells rather than manifestation of either a systemic or a CNS effects (21).
158
Table 2. Selected Peripheral Gastrointestinal Physiological Effects of Gut PGs. Data were adapted from Dajani (1). Physiological Effects
PGEs
PGFs
Prostacycline
Inhibition
No inhibition
Inhibition
Gastric Blood Flow
Stimulation
Variable
Stimulation
Gastric Mucus Secretion
Stimulation
Stimulation
Stimulation
Intestinal Bicarbonate
Stimulation
Unknown
Unknown
Active
Unknown
Active
Pancreatic Secretion
Inhibition
Unknown
Unknown
Hepatic Blood Flow
Increase
Unknown
Unknown
Increased
Increased
Increased
Contraction
Contraction
Unknown
Sphincter of Oddi
Relaxation
Unknown
Unknown
Lower Esophageal Sphincter
Relaxation
Contraction
Unknown
Gastric Acid Secretion
Gastric Mucosal Barrier
Small Intestinal Electrolytes & Water Secretion Gall Bladder Muscle
Gastric & Intestinal Cytoprotection
Active
Experimental Ulcers a
The
dosages
shown
Active
a
Active
effective
in
animal
Active
Active
cytoprotective
studies
are
a
Active well
below
their
gastric
antisecretory doses.
Table 3. Prostaglandins and Gastrointestinal Physiology. l
A direct relationship exists between altered function and Prostaglandin biosynthesis (15, 16).
l
Exogenously administered natural PGs alter physiological function.
l
Prostaglandins
depletion
cause
diseases
(e.g.,
NSAID-induced
GI
ulcer)
and
exogenous
administration of PGEs prevents and treat such ulcers (17, 18).
Prostaglandins and Central Nervous System Prostaglandins and other eicosanoids have been identified in the CNS. The synthesis of PGE2, PGD2, PGF2 alpha, PGI2, thromboxane A2 (TXA2), leukotriene C4 (LTC4), leukotriene B4 (LTB4) and other eicosanoids in the brain were welldemonstrated (Table 4; 22). Of interest is the observation that PGD2 and PGF2 alpha are
synthesized
in
large
quantity
in
the
brain
(22).
PGD2
has
recently
been
159
proposed as a mediator responsible for sleep (23). Both stimulant and depressant effects of PGs on the CNS have been reported following their injection into the cerebral ventricle and the firing rates of individual brain cells may be increased or decreased after iontrophoric applications of PGs (24). Intracerebroventricular administration of prostacyclin (PGI2) produced sedation, stupor, catatonia as well as
cataleptic
behavior
(25).
PGs
have
been
proposed
to
modulate
catecholaminergic (26), serotoninergic (27) and cholinergic (28) neurons in the CNS. There is also accumulating data suggesting possible modulatory role of PGs on dopamine mediated behavior (29). However, the evidence for a modulating role of PGs on neuronal pathways is derived from limited in-vitro studies and no studies
have
investigated
the
central
role
of
PGs
on
and
PGF2
peripheral
dopamine-
mediated GI effects.
Table 4. Prostaglandins and Central Nervous System l
Many
PGs
have
been
identified
in
the
CNS.
PGD2
alpha
are
present
in
highest
concentration in the brain.
l
Both
stimulant
and
depressive
effects
of
PGs
have
been
reported
following
their
central
administration.
l
Many pharmacological effects have been observed following intracerebral administration of PGs, but no study has ever demonstrated a specific physiological effect on the GI tract.
l
Convincing experimental data indicate that PGs function in the CNS in pathological processes such as pain, fever, drug dependence and possibly paralytic ileus.
Convincing
experimental
data
indicate
that
PGs
function
in
mostly
pathological processes in the CNS, including drug dependence, nociception, fever induction, learning and memory, and excitotoxic brain injury such as stroke and epilepsy
(30,
31).
Elevated
levels
of
PGE2,
PGF
2
,
alpha
thromboxane
B2
in
cerebrospinal fluid have been found in patients with AIDs dimentia. Abnormal central COX-2 expression had been found in patients with Parkinsons disease and Down syndrome (32). There is some emerging evidence indicating that central PGs may also be connected to an endogenous cannabinoids system as noted by the discovery that anadamide (arachidonyl ethanolamine), which is chemically an eicosanoid and is considered to possess cannabinoid agonist activity (33). However, it is beyond the scope of this paper to discuss all aspects of central PGs involvement in all pathological
processes
but
rather
focus
on
four
principal
actions
of
PGs
as
detailed below: (a) Drug dependence: The central administration of PGE2 facilitates acute
dependence in morphine treated rats, while PGF2
alpha
(acting on dopaminergic
160
neurons) Sparber
showed (34)
inconsistent
showed
attenuation
attenuation
of
of
such
dependence.
morphine-induced
Nielsen
withdrawal,
and
while
Nakagawa et al. (35) did not demonstrate any reduction of withdrawal symptoms following the intracerebral administration of PGF2alpha. Furthermore, Nakagawa et al. (35) showed that synthetic PGs acting on the prostaglandin EP3 receptor attenuated
withdrawal
jumping
in
intracerebral administration of PGF2
morphine alpha
dependent
mice,
however,
the
showed no such effect. Nechifor et al.
(36) showed that two metabolically stable chemical analogs of PGF2alpha, when administered
intraperitoneally,
reduced
several
symptoms
of
the
withdrawal
syndrome in rats with morphine-induced dependence. These observations suggest a role of central PGs in the induction of drug dependence, either directly or indirectly
via
a
modulating
effect
on
catecholaminergic,
serotoninergic
and
cholinergic neurons in the CNS. (b) Pain: Central PGs are clearly involved in pain perception and induction (31, 37). As reported by Turnbach et al. (38), the intrathecal administration of PGE2
(1-100
nmol)
or
PGF2alpha
(1-100
nmol)
produced
profound
and
dose-
dependent mechanical hyperalgesia, but only weak thermal hyperalgesia and touched-evoked allodynia in rats. Both PGs produced dose-dependent increases in response of nociceptive specific neurons to mechanical stimuli (38). (c) Inflammation: Prostaglandin E2 is the major prostanoid produced centrally and in the periphery in animal models of acute and chronic inflammation, and its formation in both locations is blocked by COX-2 inhibitors (39). The PGE2induced inhibition by COX-2 inhibitors in the brain may occur secondarily to peripheral
action
mediated
by
inhibiting
local
PGs
formation,
which
elicit
increased firing of pain fibers and consequent activation in PGs synthesis in the CNS (39). (d) Fever: The systemic administration of PGEs induces fever in laboratory animals and man via a CNS mediated mechanism of action (30, 40, 41). Pyrogens such as interleukin-1 (IL-1) act via hypothalamic release of PGs (42). Prostaglandins and Brain-Gut Relationship As of now, there are no meaningful studies, which characterized the in-vivo effect of central PGs on GI physiology such as acid secretion, GI motility and cytoprotection. Miura et al. (43) examined the receptor subtypes mediating the effects
of
PGE2
on
parasympathetic
preganglionic
neurons
that
regulate
the
activity of pelvic visceral organs using neonatal rat spinal slices, in-vitro. These investigators showed that PGE2 increased the firing frequency to depolarizing current pulses, induced after discharges and inhibited spike potential after hyperpolarization
but
did
not
affect
phasic
preganglionic
neurons.
These
results
indicate that PGE2 acting via EP1 and/or EP4 receptors modulated the excitability and/or
the
excitatory
synaptic
input
to
tonic
parasympathetic
preganglionic
161
neurons.
Clearly,
these
studies
need
to
be
repeated
in
order
to
confirm
the
neurophysiologic action of PGE2 in the gut. From involved
a
pathophysiologic
in
etiology
of
considerations,
postoperative
ileus
prostaglandins as
evident
by
may
be
also
increased
be
spinal
expression of COX-2 suggesting a primary afferent activation. This activation of primary afferents may subsequently initiate inhibitory motor reflexes to the gut, contributing to postoperative ileus (44). Given the limited available CNS information, the function of PGs in neuronal tissues rests on inferences from in-vitro studies and from the studies connected with COX inhibitors (32). The absence of specific PG receptor antagonists for E, D, F and I series has clearly hampered our understanding of the role of individual PG in the CNS as well as other tissues. We fully agree with the assessment of Morrow and Roberts (24) that there is no clear physiological role of PGs in the CNS. Furthermore, despite some indirect and preliminary evidence summarized in Table 5, there is no consistent data, which well demonstrate the involvement of PGs in the brain-gut axis.
Table 5. Prostaglandins and Brain-Gut Axis l
The effects of direct central administration of PGs on GI physiological function have not been investigated.
l
PGs
have
been
shown
to
modulate
the
release
of
dopamine
and
serotonin.
Dopamine
is
positively involved in the brain-gut axis, especially cytoprotection.
l
Available evidence indicates the PG-induced GI physiological effect is primarily mediated by peripheral rather than central action.
In summary, PGs and COX enzymes are present in and out of the CNS. Elevated levels of PG are found in few pathological processes such as fever and pain. The function of PGs in neuronal tissues rest on inferences from in-vitro studies and from studies connected with COX inhibitors. We conclude that the GI physiological and mucosal protective effects of PGs are essentially mediated by direct effects on cells or organs rather than by a direct effect on the CNS. Clearly, additional
studies
are
warranted
to
investigate
the
CNS
role
in
the
GI
physiological actions of PGs to clarify the precise role of PGs in brain-gut axis.
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Received:
November 15, 2003
Accepted:
December 18, 2003
Authors address: Esam Z. Dajani, Ph.D., FACG, IDDC Corporation, 1549 RFD, Long Grove, IL 60047-9532, USA, Phone (847) 634-9586, Fax (847) 634-3349 E-mail:
[email protected]
